Mitochondria, endothelial cell function, and vascular diseases

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Mitochondria content in EC is relatively low in comparison with those with high-energy demand. EC obtain a large proportion of energy from the anaerobic glycolytic metabolism of glucose. Those facts implicate the mitochondria in EC are unlikely to act as an energy factory but, sense the local environment the EC face and orchestrate the cellular hemostasis and function. Persistent environmental risk signals can damage mitochondria, which in turn produce excessive ROS and accelerate e EC senescence, death and dysfunction. EC serve as the first barrier of the vascular system, the dysfunction of endothelial cell is considered to be the pathological basis of various vascular diseases including atherosclerosis, diabetic vascular dysfunction, PAH and hypertension. Rescuing mitochondrial function, or “re-educating” the damaged mitochondria, has been demonstrated as potential interventions to improve vascular conditions both in animal models and in human patients. However, several interesting issues are up in the air in this field. The first issue is mitochondria-nucleus communication. Accumulating evidence have implicated that mitochondria can send signals to the nucleus, regulating the events in the nucleus. More importantly, it is interesting to see whether mitochondria signal influences epigenetic remarks in the nucleus. Acetylation and methylation of histone tails are dynamics processes regulated by histone de/acetyltransferases, methyltransferases, or demethylases. Co-factors, including flavin adenine dinucleotide (FAD), acetyl-CoA, and α ketoglutarate (α-KG), are associated with the processes of active de/methylation or de/acetylation (Minocherhomji et al., 2012). Both FAD and α-KG are known to be synthesized in mammalian mitochondria. In this regard, mitochondria are critically important for epigenetic modification in the nucleus. Altered levels of these co-factors due to mitochondrial impairment/dysfunction could have significant effects on regulation of the nuclear genome, and subsequent endothelial function. In addition, depletion of mtDNA results in significant changes in methylation pattern of a number of genes (Smiraglia et al., 2008). Vascular EC undergo senescence, apoptosis and mitophagy in disease conditions. All those processes are regulated at least in part by mitochondria. Therefore, the second question is whether mitochondria serve as pivotal modulators of those processes just as orchestrating a shadow play. Finally, with regard to mitochondria-targeted approaches, current studies are focusing on the antioxidants. It remains largely unknown the roles of dysregulated metabolites of the mitochondria in mitochondria damage and endothelial cell dysfunction. If they are important, they may serve as potential targets to “re-educate” mitochondria in EC, and subsequently serve as candidate targets for vascular diseases therapy.

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